Stereodivergent Access to Enantioenriched Epoxy Alcohols with Three Stereogenic Centers via Ruthenium-Catalyzed Transfer Hydrogenation

Article abstract of DOI:10.1021/acs.orglett.9b01789

The resolution technique of stereodivergent reaction on racemic mixtures (stereodivergent RRM) was employed for the first time in ruthenium complex catalyzed transfer hydrogenation of racemic epoxy ketones, providing a new and very simple method that allows access to enantioenriched epoxy alcohols with three stereogenic centers in a one-step fashion. The protocol features simple reaction conditions, practical operation, ability to scale up, and broad group tolerance.

Full text of DOI:10.1021/acs.orglett.9b01789

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereodivergent Access to Enantioenriched Epoxy Alcohols with
Three Stereogenic Centers via Ruthenium-Catalyzed Transfer
Hydrogenation
Zhifei Zhao,†,∥ Prasanta Ray Bagdi,†,∥ Shuang Yang,†,‡ Jinggong Liu,§ Weici Xu,*,†
and Xinqiang Fang*,†,‡
†State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Center for Excellence in
Molecular Synthesis, University of Chinese Academy of Sciences, Fuzhou 350100, China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Shanghai 200032 China
§Orthopedics Department, Guangdong Provincial Hospital of Traditional Chinese Medicine, No. 111 Dade Road, Guangzhou
510120, China
S
* Supporting Information
ABSTRACT: The resolution technique of stereodivergent
reaction on racemic mixtures (stereodivergent RRM) was
employed for the first time in ruthenium complex catalyzed
transfer hydrogenation of racemic epoxy ketones, providing a
new and very simple method that allows access to
enantioenriched epoxy alcohols with three stereogenic centers
in a one-step fashion. The protocol features simple reaction
conditions, practical operation, ability to scale up, and broad
group tolerance.
Scheme 1. State-of-the-Art EEA Synthesis
xploitation of new methods realizing the rapid access to
Ehighly important chiral building blocks is a popular research
topic in both academic and industrial domains. Enantioenriched
epoxy alcohols (EEA) with three stereogenic centers serve as
important building blocks and starting materials in a variety of
fields such as organic synthesis, chemical engineering, medicinal
industry, and agrochemical production.1 The state-of-the-art
synthesis of such molecules mainly relies on three strategies. As
shown in Scheme 1a, epoxidation of stoichiometric chiral allylic
alcohols and reduction of chiral epoxy ketones are commonly
used methods to produce the target EEAs, but the limited
commercial availabilities of these chiral reagents prevent the
wide utility of such a strategy, and in some cases, the
diastereoselectivities of the reaction are hard to control.2
Asymmetric catalytic approaches are more attractive to achieve
the synthesis of EEAs with three stereocenters, but it is relatively
surprising that to date extremely fewer one-step asymmetric
catalytic methods have been developed to achieve this purpose,
and in most cases multiple steps are needed, which result in
relatively lower atom economy and higher cost.3 A selected four-
step asymmetric catalytic synthesis route is shown in Scheme
1b.3c To date, the most frequently used catalytic strategy
allowing access to EEAs is still kinetic resolution of racemic
allylic alcohols via asymmetric epoxidation, albeit with 50%
theoretical yield.4 The representative milestone report was
introduced by Sharpless in 1981 (Scheme 1c).4b It can be seen
that despite all these achievements, new methods leading to the
rapid synthesis of EEAs are still highly needed.
The strategy of divergent reactions on racemic mixtures
(divergent RRM), proposed by Kagan in 2001,5 has been widely
accepted as a powerful technique allowing access to chiral
molecules directly using racemic substrates.5,6 The strategy is
advantageous in assembling structurally diversified molecules
and shortening the synthetic routes in complex molecule
Received: May 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
synthesis such as natural products.7 However, to the best of our
knowledge, this technique has not been used to achieve the one-
step synthesis of EEAs using hydrogenation of easily available
racemic epoxy ketones. The challenge is that the inherent
substrate preference for the product stereoselectivity must be
overcome. As illustrated in Scheme 2, a matched case favors both
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Challenge of Overcoming Substrate Preference in
Divergent RRM
2a/3a
entry cat. (mol %) temp (°C), solvent, time (h) yield (%)
ee (%)
1
2
3
4
5
6
7
8
A(5)
A(5)
70, DMF, 24
70, DCE, 28
70, THF, 26
56/15
54/28
55/22
54/17
62/14
58/24
22/38
48/32
47/34
26/32
38/35
39/36
42/48
43/45
51/40
39/33
35/49
36/35
39/35
46/45
31/34
45/48
38/39
41/99
53/97
53/97
55/99
60/99
48/99
55/99
75/89
80/90
76/92
79/94
76/97
84/83
88/84
86/93
80/90
86/69
81/89
84/87
90/98
87/89
82/83
81/92
A (5)
A (5)
A (5)
A (5)
A (5)
B (5)
B (5)
B (5)
C (5)
C (5)
C (5)
C (5)
C (5)
C (2)
C (2)
C (2)
C (2)
C (2)
C (2)
C (2)
C (2)
40, CH2Cl2, 24
40, dioxane, 24
40, DMF, 24
40, no solvent, 18
40, dioxane, 30
40, DMF, 30
40, no sovlent, 24
40, THF, 12
40, DMF, 12
40, iPrOH, 14
40, dioxane, 15
40, no solvent, 10
40, DMF, 12
40, CH2Cl2, 15
40, THF, 12
40, dioxane, 15
40, no solvent, 12
40, DCE/DMF, 16
40, iPrOH/DMF, 18
40, dioxane/DMF, 16
the substrate preference and the catalyst preference, thus leading
to the formation of chiral product 2; however, a mismatched pair
produces not only the catalyst-controlled product 3 but also
minor product ent-2 due to the inherent substrate preference,
thereby resulting in the enantioselectivity erosion of product 2.
In the worst case, both enantiomers of the substrate would not
match the chiral catalyst and provide both products with low ee
values.6a
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
In this context, we envisioned using transfer hydrogenation8
of racemic epoxy ketones through the technique of divergent
RRM to realize the rapid synthesis of EEAs (Scheme 1d). If
successful, this will provide one of the most simple and direct
methods to achieve the above purpose. To our pleasure, the
protocol could afford two separable diastereoisomers of EEAs in
a one-step fashion, and the reaction employs very simple
reaction conditions, tolerates various functional groups, and
constitutes a complementary method to the classical kinetic
resolution approach. Herein we report the results.
a
Reaction conditions: racemic 1a (0.2 mmol), HCO2H/Et3N (1:3 v/
v, 1 mL), solvent (1 mL), under argon atmosphere; all yields are
isolated yields and were based on 1a; ee values were determined via
HPLC analysis on a chiral stationary phase.
As shown in Table 1, we selected easily available racemic
trans-1a as the model substrate for the study, and Noyori-type
ruthenium complexes A−C9 were surveyed. The first test of
catalyst A9a (5 mol %) in DMF led to the formation of both
isomers but with 2a as the major one and with lower ee value
(Table 1, entry 1), indicating the strong substrate control
mentioned in Scheme 2. Changing the solvents to DCE and
THF did not give better results (Table 1, entries 2 and 3), and
lowering the temperature to 40 °C still could not overcome the
substrate preference, leading to the formation of 2a as the major
product (Table 1, entries 5−6). The reaction without additional
solvent also failed (Table 1, entry 7). Catalyst B9b showed better
ability in suppressing the substrate control, and 2a can be
formed with up to 80% ee (Table 1, entries 8−10). Then we
found that catalyst C, reported initially by Ikariya,9c showed
slightly better results considering the product distribution
and 45% yields, with 90% and 98% ee, respectively (Table 1,
entry 20). We also tested the reaction using mixed solvents, but
inferior results were afforded (Table 1, entries 21−23);
therefore, the conditions shown in entry 20 were established
as the optimal ones.
Using the optimal conditions, we investigated the substrate
scope and limitations of the protocol. Variation of R1 unit using
chloro- or fluoro-substituted phenyl groups resulted in no
obvious influence on the results, delivering the corresponding
stereoisomers with excellent enantioselectivities (Scheme 3, 2b/
3b, and 2c/3c). Naphthyl group-substituted racemic epoxy
ketone can also tolerate the reaction conditions, albeit with
moderate ee values (Scheme 3, 2d/3d). Then we checked the
alteration of R3 moiety using the 4-ClC6H4 group, and products
2e and 3e were formed with 83% and 98% ee, respectively
(Scheme 3, 2e/3e). Similarly, when R2 unit was replaced by 3-
chloro-substituted phenyl ring, the reaction afforded 2f and 3f
with good level of enantioselectivities (Scheme 3, 2f/3f).
Variation of both R1 and R2 moieties simultaneously proved
possible, producing the corresponding products in high level of
enantioselectivity (Scheme 3, 2g/3g, 2h/3h, and 2i/3i).
Furthermore, changing both R1 and R3 units was also possible,
i
(Table 1, entries 11 and 12), and the use of PrOH could
produce 2a and 3a in comparable yields with good level of
enantioselectivity (Table 1, entry 13). Similar results were
observed using dioxane as the solvent (Table 1, entry 14), and
the reaction in the absence of additional solvent could also
perform well (Table 1, entry 15). Then we decreased the catalyst
loading to 2 mol %, and different levels of product
enantioselectivity were detected with the variation of solvents
(Table 1, entries 16−19). To our pleasure, the reaction without
additional solvent using 2 mol % of C provided 2a and 3a in 46%
B
DOI: 10.1021/acs.orglett.9b01789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
stereoinduction was observed when a substrate with an aliphatic
R2 group was used (Scheme 3, 2o/3o).
Scheme 3. Substrate Scope
Somewhat to our surprise, the protocol shows higher
reactivity toward trans-substrates when both trans- and cis-
epoxy ketones are used. As shown in Scheme 4, under the
Scheme 4. Reaction Using a Mixture of trans/cis-1b
standard conditions, only trans-1b underwent the reduction, and
cis-1b displayed almost no reactivity. The possible reason is that
the cis-aryl group blocks the hydride attack on the carbonyl units.
We were glad to find that the scale-up reaction could work
well, and no erosions on the product enantioselectivity were
detected (Scheme 5a). Furthermore, the products can be easily
Scheme 5. Scale-up Reaction and Synthetic Applications
transformed to other synthetically useful building blocks. As
shown in Scheme 5b, the oxidation of 3c led to epoxy ketone 4a
in 90% yield, and the ring opening using NaN3 resulted in the
formation of 4b without erosion of the ee value. Moreover, the
protection of the OH group of 3c afforded 4c with excellent
enantioselectivity.
On the basis of the above experiments and the literature
reports, we proposed the possible reduction modes of the
process. As shown in Scheme 6, using racemic 1b as the model
Scheme 6. Proposed Reaction Modes
a
Racemic 1 (0.2 mmol), C (2.7 mg, 2 mol %), HCO2H/Et3N (1:3 v/
v, 1 mL), under argon atmosphere; all isolated yields were based on 1;
ee values were determined via HPLC analysis on a chiral stationary
b
phase. C (1.5 mol %) was used.
producing 2j and 3j with moderate and excellent ee, respectively
(Scheme 3, 2j/3j). Moreover, EEAs with two stereocenters
could also be formed with good enantioselectivities (Scheme 3,
2k/3k). When R1 was set as the aliphatic methyl group, the
reaction proceeded smoothly, allowing access to 2l and 3l with
good ee values (Scheme 3, 2l/3l). Meanwhile, racemic
substrates with aliphatic ketone moieties also worked well, and
the corresponding products were obtained with moderate to
excellent ee (Scheme 3, 2m/3m and 2n/3n). Unfortunately, low
substrate, two six-membered transition states between the
ketone group and the Ru complex are proposed to explain the
formation of the products (Scheme 6, TS-1 and TS-2).10 In
more detail, the (2S,3R)-enantiomer of 1b will afford product 2b
under catalyst-controlled selective reduction, and similarly,
product 3b will be produced from the (2R,3S)-enantiomer of
1b.
C
DOI: 10.1021/acs.orglett.9b01789
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have developed a new method allowing
access to enantioenriched epoxy alcohols in a one-step fashion.
The protocol employs ruthenium-catalyzed direct-transfer
hydrogenation on racemic epoxy ketones, and the resolution
technique of divergent RRM was found feasible in this process.
Different from the conventional classical kinetic resolution of
allylic alcohols, this method displays 100% utilization of starting
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b01789.
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Accession Codes
CCDC 1908563 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: xqfang@fjirsm.ac.cn.
*E-mail: weicixu@sina.com.
(8) For selected reviews, see: (a) Zassinovich, G.; Mestroni, G.;
Gladiali, S. Chem. Rev. 1992, 92, 1051. (b) de Graauw, C. F.; Peters, J.
A.; van Bekkum, H.; Huskens, J. Synthesis 1994, 1994, 1007. (c) Noyori,
R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97. (d) Palmer, M. J.; Wills,
ORCID
Xinqiang Fang: 0000-0001-8217-7106
Author Contributions
∥Z.Z. and P.R.B. contributed equally.
Notes
̀
M. Tetrahedron: Asymmetry 1999, 10, 2045. (e) Pamies, O.; Backvall, J.-
E. Chem. - Eur. J. 2001, 7, 5052. (f) Everaere, K.; Mortreux, A.;
Carpentier, J.-F. Adv. Synth. Catal. 2003, 345, 67. (g) Gladiali, S.;
̈
Alberico, E. Chem. Soc. Rev. 2006, 35, 226. (h) Samec, J. S. M.; Backvall,
The authors declare no competing financial interest.
J.-E.; Andersson, P. G.; Brandt, P. Chem. Soc. Rev. 2006, 35, 237.
(i) Ikariya, T.; Blacker, A. J. Acc. Chem. Res. 2007, 40, 1300. (j) Blacker,
A. J. In Handbook of Homogeneous Hydrogenation; de Vries, J. G.,
Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, 2007. (k) Wang, C.; Wu,
X.; Xiao, J. Chem. - Asian J. 2008, 3, 1750. (l) Ikariya, T. Bull. Chem. Soc.
Jpn. 2011, 84, 1. (m) Bartoszewicz, A.; Ahlsten, N.; Martín-Matute, B.
Chem. - Eur. J. 2013, 19, 7274. (n) Slagbrand, H.; Lundberg, H.;
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21871260), the strategic priority research
program of the Chinese Academy of Sciences (XDB20000000),
the Chinese Recruitment Program of Global Experts, Fujian
Natural Science Foundation (2018J05035), and China Post-
doctoral Science Foundation (2018M630734).
̌
̌
Adolfsson, H. Chem. - Eur. J. 2014, 20, 16102. (o) Stefane, B.; Pozgan,
F. Catal. Rev.: Sci. Eng. 2014, 56, 82. (p) Wang, D.; Astruc, D. Chem.
Rev. 2015, 115, 6621. (q) Foubelo, F.; Najera, C.; Yus, M. Tetrahedron:
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Asymmetry 2015, 26, 769. (r) Echeverria, P. G.; Ayad, T.; Phansavath,
P.; Ratovelomanana-Vidal, V. Synthesis 2016, 48, 2523. (s) Chen, Z.-P.;
Zhou, Y.-G. Synthesis 2016, 48, 1769.
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Org. Lett. XXXX, XXX, XXX−XXX